An important focus of my work is development of chimeric antigen receptor T cell therapies for multiple myeloma, which is a usually incurable malignancy of plasma cells. A major obstacle to development of CAR-expressing T-cell therapies for multiple myeloma is the lack of suitable target antigens. Anti-BCMA CARs: I have recently designed and constructed two CARs that specifically recognize B-cell maturation antigen (BCMA). BCMA has a very restricted expression pattern in normal tissues, but BCMA is expressed on the malignant plasma cells of multiple myeloma.7 The BCMA specific CARs that I have constructed specifically recognize multiple myeloma cell lines in functional assays in vitro. Anti-BCMA CAR-expressing T cells can eradicate myeloma tumors in mice. An extensive analysis of BCMA expression in normal human tissues by immunohistochemistry and quantitative PCR has been conducted. Except for expression by normal plasma cells, BCMA expression was not detected in nomal human organs by immunohistochemistry. a paper and an abstract on this project have been published in the past year. A clinical trial of anti-BCMA-CAR-transduced T cells for treating advanced multiple myeloma has been opened for enrollment since September, 2014. So far 12 patients have been treated and are evaluable for response. There have been impressive responses on this trial, which were the first demonstrated examples of elimination of measurable multiple myeloma by CAR T cells. This work led to a publication in the journal Blood in 2016. In conjunction with Bluebird Bio, Inc. We have developed a new anti-BCMA CAR that Bluebird licensed from the NCI. This new CAR was developed in part in my laboratory. This new CAR is being tested in a multicenter trial of which I participate as a site PI.. The NCI is the lead site for this trial with 5 of 6 patients treated on the trial so far having been treated at the NCI. The trial is showing promising results with the last 3 patients treated obtaining objective remissions. We have a project looking at how changes in the structure of the hinge region of CARs can be quite important in determining in vivo efficacy of CARs. We have been focusing on improving the structure of an anti-BCMA CAR over the past year, and great progress has been made in determining the optimal hinge region of anti-BCMA CARs. Some promising candidate antigens have been identified, and initial evaluation of these antigens has begun.